The key mediators involved in myocardial endoplasmic reticulum stress induced by ischaemia reperfusion injury in rats

Abstract

Objective: Endoplasmic reticulum stress (ERS) occurs throughout the pathological process of myocardial ischaemia reperfusion injury (MIRI); however, the key mediators involved in the biological processes of ERS or that can influence the outcomes of ischaemia reperfusion injury (IRI) are unclear. To identify the differentially expressed genes (DEGs) encoding promising mediators in rat hearts in the context of MIRI, gene profiles were mined through transcriptome analysis. Methods: By searching the Gene Expression Omnibus (GEO) database, a suitable GEO dataset was identified in the context of MIRI with 24 h reperfusion after 45 min ischaemia in rats. DEGs were extracted and analysed with R studio, and the properties of those DEGs were elucidated by utilizing protein‒protein-interaction (PPI), Cytoscape, GO and KEGG bioinformatics techniques. The potential hub genes in the first cluster of the DEG dataset were retrieved and verified by basal experiments. Results: By searching the target dataset GSE122020, 1647 mRNAs, including 790 upregulated and 857 downregulated genes, were found in the datasets with criteria of | fold change ≥ 1.2 and p value <0.05. The upregulated and downregulated genes were primarily involved in the “positive regulation of cytokine production”, “regulation of inflammatory response” and “response to pheromone” biological processes. Most of them were mainly correlated with the MAPK, Ras and calcium signalling pathways. In particular, 15 DEGs were found to be involved in the ERS signalling pathways, including Bfar, Itpr1, Srpx, Hspa1b, Usp25, Jun, Casp12, Eif2ak2, Casp4, Trim25, Ifng, Atf3, Hspa1a, Ppp1r15a, and Creb3. Through analysis with the MCODE plugin in Cytoscape, six genes, Atf3, Ppp1r15a, Casp12, Eif2ak2, Ifng, and Hspa1a, were identified as hub genes by the K-means algorithm from Cluster 1. In the in vivo MIRI model, the six genes mentioned above exhibited significant mRNA overexpression in the left anterior descending coronary artery ligation (LAD) model in rats. Conclusions: Altogether, the present study identified six potential DEGs involved in ERS induced by MIRI, which could be therapeutic targets in dealing with IRI-related ERS.